Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency

Muhammad Wasif Saif, Robert B. Diasio

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Background: 5-Fluorouracil (5-FU), an analog of uracil, is one of the most commonly used chemotherapeutic agents and like other agents has a narrow therapeutic index limited by toxicity. Compared to previous attempts, uridine triacetate (Vistogard) has shown to increase the potential efficacy of 5-FU by allowing administering a higher dose and decreasing the toxicity. Recently, Vistogard received orphan drug designation from the FDA as an antidote in the treatment of 5-FU poisoning and from the European Medicines Agency as a treatment for 5-FU overdose. However, no data have been published to date in humans who were rescued by this agent following severe toxicity associated with 5-FU due to dihydropyrimidine dehydrogenase (DPYD) deficiency, the enzyme which is responsible for the elimination of approximately 80 % of the administered dose of 5-FU. Patients and methods: We identified two patients with advanced pancreatic cancer who were referred to us for testing of DPYD status following severe toxicity associated with 5-FU administered at a dose of 1400 mg/m2 weekly bolus high-dose 5-FU followed by oral uridine triacetate as a part of a clinical trail. One patient developed grade 3 thrombocytopenia and grade 3 skin rash that resolved with discontinuation of 5-FU and supportive care, while second patient developed grade 4 thrombocytopenia, grade 3 coagulopathy and grade 3 neurological toxicity with a fatal outcome. DPYD status was evaluated as we have previously published. Results: The first patient was found to have an abnormally low DPYD activity of 0.087-nmol/min/mg protein by radioisotopic assay (reference normal range 0.182–0.688 nmol/min/mg protein). Because of pancytopenia, DPYD enzyme activity could not be assessed in patient 2; genotypic analysis of DPYD during autopsy revealed the presence of the heterozygous mutation, IVS14+1 G>A, DPYD*2A, now recognized as the most common cause of DPYD deficiency. Conclusion: These two patients present the first two cases of DPYD deficiency that had either delay in severe toxicity or recovered from severe toxicity as they received oral Vistogard as a part of the conical trial. Toxicity was delayed in both patients by a mean of 3.5 weeks (range 3–4 weeks), indicating that Vistogard might be able to delay 5-FU toxicity despite higher doses than standard bolus dose of 5-FU used in gastrointestinal malignancies and the appearance of a potentially less toxic adverse effect of 5-FU at an unusual site (cutaneous) in one patient. The role of uridine triacetate with 5-FU in DPYD-deficient patients needs further investigation.

Original languageEnglish (US)
Pages (from-to)151-156
Number of pages6
JournalCancer chemotherapy and pharmacology
Issue number1
StatePublished - Jul 1 2016


  • 5-Fluorouracil
  • DPYD gene
  • Fluoropyrimidines
  • PN401
  • Uridine

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)


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